Syndromes of chromosomal breakages

Immunodeficiency and chromosomal instability are markers of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which together with Bloom's syndrome, the pigmentary xeroderma is included in the group of syndromes with chromosomal instability. Genes whose mutations cause the development of AT and NBS are ATM (Ataxia-Teleangiectasia Mutated) and NBSl, respectively. ATM encodes the synthesis of the eponymous kinase, and NBSl - nibrin. Both proteins are involved in the repair of two-strand DNA ruptures and the regulation of the cell cycle. The cells of patients with A-T and NBS have a similar phenotype and are characterized by increased sensitivity to radiation, cell cycle defects, clinical manifestations and immunological disorders have significant differences, although both diseases show an increased incidence of malignant tumors and spontaneous chromosomal instability and chromosomal breakages, involving mainly 7 and 14 chromosomes.

It is known that the cell cycle is divided into 4 phases: mitosis (M) and DNA synthesis (S), separated by two interruptions of G1 and G2. The sequence of the cell cycle is as follows: G1-S-G2-M. After the action of ionizing radiation, double-strand breaks of DNA occur. If there is DNA repair, then the cell cycle is restored, if not, the cell is killed by apoptoa or a mutant clone develops. Normally, the cell cycle under the action of radiation can be blocked at two critical points-the transition from G1 to S and / or from G2 to the M phase. At A-T and NBS, control of the cell cycle at critical points is impaired. The ATM protein plays a critical role in activating the ways of regulating the cell cycle that are realized in both G1 and G2-phases. The NBS1 gene encodes a nibrin protein, which, like ATM, is involved in the regulation of the cell cycle.

Normally, double-stranded DNA breaks occur during V (D) J recombination of the immunoglobulin and T-cell receptor genes, during crossing-over, with meiosis. Processes reminiscent of the recombination of immunoglobulin genes occur during the maturation of neurons of the brain. Obviously, it is with defects in DNA repair that many clinical and immunological manifestations in patients with NBS and A-T are associated in these cases, such as immunoglobulin synthesis, the functions of the genital organs and the nervous system.

It is extremely rare to combine a classic phenotype of AT with microcephaly and ATM mutations, and this syndrome is called "AT-Fresno". In fact, AT-Fresno is a phenotype that reflects the association of AT with Nijmegen's syndrome.